Host-Pathogen Interaction as a Novel Target for Host-Directed Therapies in Tuberculosis

Abstract

Tuberculosis (TB) has been a transmittable human disease for many thousands of years, and M. tuberculosis is again the number one cause of death worldwide due to a single infectious agent. The intense 6-to 10-month process of multi-drug treatment, combined with the adverse side effects that can run the spectrum from gastrointestinal disturbances to liver toxicity or peripheral neuropathy are major obstacles to patient compliance and therapy completion. The consequent increase in multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) cases requires that we increase our arsenal of effective drugs, particularly novel therapeutic approaches. Over the millennia, host and pathogen have evolved mechanisms and relationships that greatly influence the outcome of infection. Understanding these evolutionary interactions and their impact on bacterial clearance or host pathology will lead the way toward rational development of new therapeutics that favor enhancing a host protective response. These host-directed therapies have recently demonstrated promising results against M. tuberculosis, adding to the effectiveness of currently available anti-mycobacterial drugs that directly kill the organism or slow mycobacterial replication. Here we review the host-pathogen interactions during M. tuberculosis infection, describe how M. tuberculosis bacilli modulate and evade the host immune system, and discuss the currently available host-directed therapies that target these bacterial factors. Rather than provide an exhaustive description of M. tuberculosis virulence factors, which falls outside the scope of this review, we will instead focus on the host-pathogen interactions that lead to increased bacterial growth or host immune evasion, and that can be modulated by existing host-directed therapies.

Longer-Term Omega-3 LCPUFA More Effective Adjunct Therapy for Tuberculosis Than Ibuprofen in a C3HeB/FeJ Tuberculosis Mouse Model

“…This approach, amongst other mechanisms, aims to improve the host defence mechanisms, and/or modulate excessive inflammation, by altering the host’s response, rather than targeting the Mtb itself ( 36 , 37 ). Recently, much research was done determining the effects of various repurposed drugs as adjunctive agents ( 4 , 38 , 39 ), including n-3 LCPUFAs ( 17 , 40 , 41 ) and ibuprofen ( 10 , 42 ), with varying results in the field of TB.…”

“…Tuberculosis causes an inflammatory reaction that damages the surrounding tissue, causing significant morbidity ( 2 , 3 ). Host cellular immune responses are exploited ( 4 ) to promote the accumulation of permissive phagocytic cells while delaying activation of the acquired responses in TB ( 5 , 6 ). Thus, therapy targeted towards modulating host inflammatory pathways to reduce abnormal or unwarranted inflammation and lung tissue destruction is a plausible host-directed intervention in TB treatment ( 7 – 9 ).…”

Adjunct n-3 Long-Chain Polyunsaturated Fatty Acid Treatment in Tuberculosis Reduces Inflammation and Improves Anemia of Infection More in C3HeB/FeJ Mice With Low n-3 Fatty Acid Status Than Sufficient n-3 Fatty Acid Status

“…Tuberculosis (TB) disease is considered as an example of host immune failure ( 1 ), because of the ability of the pathogen to manipulate or evade the cellular immune responses to favor its persistence ( 2 ). TB is associated with a host inflammatory response, which results in injury to the surrounding tissue, causing significant chronic pulmonary impairment and morbidity ( 3 – 5 ).…”

“…Proinflammatory lung cytokines; interleukin-6 (IL-6) (p = 0.011), IL-1α (p = 0.039), MCP1 (p = 0.003), MIP1α (p = 0.043), and RANTES (p = 0.034); were lower, and the antiinflammatory cytokine IL-4 (p = 0.002) and growth factor GMCSF (p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that INTRODUCTION Tuberculosis (TB) disease is considered as an example of host immune failure (1), because of the ability of the pathogen to manipulate or evade the cellular immune responses to favor its persistence (2). TB is associated with a host inflammatory response, which results in injury to the surrounding tissue, causing significant chronic pulmonary impairment and morbidity (3)(4)(5).…”

Effective host-directed therapy for tuberculosis by targeted depletion of myeloid-derived suppressor cells using a diphtheria toxin-based fusion protein

“…Host-directed therapies (HDTs) have the potential to reduce TB associated tissue damage and enhance host-mounted immunity, and they are insensitive to the antibiotic resistant state of the pathogen. In light of these attractive qualities, HDTs have been studied more intensively as an approach to adjunctive TB chemotherapy [2][3][4][5].…”